The patients receiving Lactobacillus GG in the ORS gained, during the first 24 hours, 220 ± 120 g (range, 8830 ± 2620 g to 9050 ± 2630 g). Those receiving only ORS gained, in the same period, 160 ± 200 g (range, 8750 ± 2790 g to 8910 ± 2680 g). Similar data were obtained when subdividing the patients according to cause of diarrhea. Thus, although children receiving Lactobacillus GG in ORS had a better average weight gain, it was not statistically significant.
Duration of Hospital Stay
The duration of hospital stay in hours is reported in Figure 5. Children receiving the ORS containing Lactobacillus GG stayed in the hospital for 78.8 ± 22.2 hours, whereas their counterparts were in the hospital for 96.3 ± 21.4 hours (P = 0.04). When considering the groups according to cause, it is evident that the clearest advantage was seen in the children affected by rotavirus. Hospital stay lasted 76.5 ± 15 hours in Lactobacillus GG–treated patients versus 97.9 ± 16.5 hours in control patients (P = 0.04). Although the mean duration of hospital stay also appeared to be shorter in the Lactobacillus GG–treated patients in the group of children with either an invasive pathogen or diarrhea of unknown origin, these differences were not statistically significant.
The use of lactic acid bacteria to treat human diseases is not a new concept (2,3). In fact, lactobacilli are among the most common bacterial species used to promote health and counteract intestinal infections. Among them, Lactobacillus rhamnosus strain GG (ATCC 53103) is by far the most widely investigated (4). This strain, with a capacity of transiently colonizing the human gastrointestinal tract that has been well established (5), has been shown to have a number of diverse, potentially beneficial, biologic effects and, in several clinical trials, to be effective in the prevention (6,7) and/or treatment of acute diarrheal disease in children (reviewed in [8,9]) and in adults (reviewed in ). However, although the effect of the probiotic is now considered well established in treating acute diarrheal disease due to rotavirus enteritis, the efficacy or inefficacy of this agent in ameliorating bacterial enteritis is not clear. Most clinical trials have been conducted in patients populations overwhelmingly composed of rotavirus-affected children (11–18). Furthermore, in reports in which a portion of the children studied were affected by likely bacterial pathogens (i.e., patients with bloody diarrhea and/or dysentery [19,20]) or in which a subset of patients were found to be affected by bacterial pathogens (18), the efficacy of the probiotic was doubtful. In our series, we confirmed in a large sample the substantial inefficacy of Lactobacillus GG in proven bacterial infectious diarrhea. In fact, in a series of 53 children with invasive pathogens (i.e., diarrhea caused by Salmonella, Shigella, Campylobacter, Yersinia, or Entamoeba), we found no difference in the duration of diarrhea between Lactobacillus GG–treated and placebo-treated groups. However, it is of interest to note that in the subset of patients in whom stools yielded no identifiable pathogens (a total of 99 children), the administration of Lactobacillus GG in the ORS induced a significant reduction of diarrheal duration. Because the Lactobacillus GG was shown to be effective in the patients with rotavirus diarrhea, we may then speculate that the success of the probiotic therapy in the patients with no identifiable pathogen may be explained by its efficacy against a pathogen of unidentified viral origin. Thus, it would appear that this particular strain of lactic acid bacteria is able to prevent and counteract the pathophysiological changes arising in the small bowel as a result of a viral infection but is less effective against those arising as a consequence of an invasive bacterial infection in the large intestine.
We can only speculate on the reason for this. Mack et al. (21) have recently presented evidence that in intestinal epithelial cells in vitro probiotic bacteria can enhance the expression of mRNA for two predominant mucins, MUC2 and MUC3. Such glycoproteins are known to have a protective role versus intestinal infections, and this mechanism may have a role in probiotic-induced protection from viral agents. Mucinase-producing bacteria, on the other hand, would effectively overcome this preventive mechanism.
In our experimental design, Lactobacillus GG was present in the ORS, a previously unreported way of administering the probiotic. We thought this innovative approach could guarantee an early colonization with the bacteria, thereby offering the most effective way of showing its efficacy. Additionally, because the intake of ORS clearly varies with the degree of dehydration, having the probiotic in the ORS would provide a means of delivering doses of the microorganism proportionate to the severity of the dehydration. Most patients did not continue to take appreciable amounts of ORS after the first 24 hours. In fact, on average, only approximately 300 ml in total was taken in after that time in both groups. Thus, intake of Lactobacillus GG can be assumed to have been 3 × 1010 CFU during the first 24 hours (approximately 1.5 × 1010 CFU during the first 4 hours), but only 1010 CFU during the entire course of the diarrheal episode.
Nevertheless, the efficacy of this approach in rotavirus-affected patients was similar to that previously reported in providing higher, more continuous doses 12,13,15,16). A recent report by Rautanen et al. (17) shows that early administration of Lactobacillus GG is effective, and that even a single early dose might be maximally effective, possibly as a result of a lasting colonization.
A result that in our opinion was of great interest is the dramatic reduction of the percentage of patients with a prolonged diarrheal episode. In the control population, more than 10% of the children had diarrhea for more than 7 days, whereas less than 3% of the treated children had such a prolonged course. The risk of having diarrhea for more than a week was found to be reduced almost four times in the Lactobacillus GG–treated group. These data show the capacity of the probiotic in helping prevent a protracted course, one of the most feared events in acute-onset diarrhea in children. Although we do not know the mechanism of prevention, it is tempting to speculate that the improved gut barrier function that Lactobacillus GG has shown in the animal (22), as well as its demonstrated anti-inflammatory effect in patients with food allergy (23) could have been contributing factors.
Finally, it is noteworthy that in our series of patients, mostly in hospitals, the length of hospital stay was markedly and significantly reduced by the use of Lactobacillus GG in ORS. This finding, mainly because of the clear effect on the duration of hospital stay for rotavirus patients, greatly adds to the benefits of this treatment by allowing a marked reduction in hospital costs as well as a diminished risk of hospital spread of rotavirus infection.
In summary, the data we present allow the following major conclusions to be drawn.
1. Lactobacillus GG can be safely administered in the ORS used in the initial rehydration of children with acute diarrhea of different origins.
2. This intervention results in a shorter duration of diarrhea. The effect is more evident in, but not limited to, rotavirus-positive patients.
3. Children who receive Lactobacillus GG have a markedly reduced chance of having diarrhea lasting more than a week than do their control counterparts.
4. Duration of hospital stay is almost 1 day less in patients receiving Lactobacillus GG in ORS.
In conclusion, we think that the current approach calling for use of hypotonic solutions (1) and early refeeding (24,25) in European children could be integrated with the use of Lactobacillus GG in the ORS to optimize the approach to infants and children who have acute-onset diarrhea.
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Keywords:© 2000 Lippincott Williams & Wilkins, Inc.
Children; Diarrhea; Infantile diarrhea; Lactobacillus GG; Probiotics; Rehydration